INSTITUTO DE QUIMICA Y FISICOQUIMICA BIOLOGICAS "PROF. ALEJANDRO C. PALADINI"
Unidad Ejecutora - UE
capítulos de libros
Effects of Growth Hormone (GH) Overexpression in Signaling Cascades Involved in Promotion of Cell Proliferation and Survival
GONZALEZ, LORENA; MIQUET, JOHANNA GABRIELA; SOTELO, ANA ISABEL
Contemporary Aspects of Endocrinology
In Tech- Open Access Publisher
Lugar: Rijeka; Año: 2011; p. 73 - 98
Effects of Growth hormone (GH) overexpression on signaling cascades involved in promotion of cell proliferation and survival. Growth hormone is a pituitary hormone involved in longitudinal growth promotion and metabolic processes. GH also affects metabolism, cardiac and immune function, mental agility and aging. Currently, GH is being used therapeutically for a variety of clinical conditions including promotion of growth in short statured children, treatment of adults with GH deficiency and HIV-associated wasting. Moreover, several alternative uses of GH have been advertised, such as for body-building, for the treatment of obesity, and as the ?fountain of youth? to prevent aging, applications that have not been approved. However, several side effects have been attained to the chronic use of this hormone, among them insulin resistance and tumorogenesis. GH overexpression has been associated with cancer in animal models as well as in humans; indeed, acromegalic patients show an increased incidence of this pathology (Webb et al. 2002; Jenkins 2004; Siegel & Tomer 2005). Moreover, proliferative diseases in humans have been associated with the overexpression of GH (Raccurt et al. 2002). Transgenic mice overexpressing GH are more susceptible to develop cancer (Orian et al. 1990; Wanke et al. 1991; Snibson 2002). On the contrary, absence or low GH levels are associated with reduced tendency to develop malignancies spontaneously (Anisimov 2001; Ikeno et al. 2003) or in response to administration of carcinogens (Styles et al. 1990; Pollak et al. 2001). In particular, mice that overexpress GH present hepatomegaly and have an increased tendency to develop hepatocellular carcinoma (HCC) at advanced ages (Snibson 2002; Bartke 2003). Throughout lifespan, transgenic mice present high levels of hepatocellular replication, followed by the onset of hepatic inflammation, fibrosis, and cirrhosis, in many cases progressing to hepatocarcinoma (Orian et al. 1990, Snibson et al. 1999, Snibson 2002). The preneoplastic pathology in liver of GH-transgenic mice is similar to that present in humans at high risk of developing hepatic cancer (Snibson 2002, Thomas & Zhu 2005). In humans, patients with hepatic alterations that lead to HCC present high levels of GH. Circulating insulin like growth factor I (IGF-I) levels, which are primarily regulated by GH action in the liver, as well as hepatic IGF-I mRNA content, are increased in GH-transgenic mice (Mathews et al., 1988; Sotelo et al., 1998). However, even when IGF-I has been widely associated with cancer development, the action of GH on hepatocytes resulting in cytological alterations would be direct rather than IGF-I-mediated, as IGF-I-overexpressing transgenic mice do not exhibit liver pathology (Quaife et al, 1989; Bartke, 2003). GH binding to its receptor (GHR) triggers enhanced association and activation of a tyrosine kinase, namely JAK2, which subsequently phosphorylates diverse signaling mediators (Waters et al. 2006; Lanning & Carter-Su 2007). Three major signaling systems are activated in response to GH: the signal transducers and activators of transcription (STATs), the phosphatidyl-inositol 3?-kinase/protein kinase B (PI3K/AKT), and mitogen activated protein kinases (MAPK) ERK1/2 signaling pathways. These signal transduction pathways are related to the induction of cellular growth, proliferation, and survival, as well as to protein, carbohydrate and lipid metabolism. GH not only induces the activation of its own receptor but also induces the expression and activation of the epidermal growth factor receptor (EGFR), a member of the ErbB family that has been widely associated to development and progression of cancer. To help reveal previous unrecognized functions of GH, better understand the known actions of GH, and predict adverse consequences that are often associated with exogenous GH administration, it is essential to establish the long-term safety aspects of GH-treatment. This would imply, among other issues, careful delineation of biochemical and molecular mechanisms whereby GH induces its diverse effects. This chapter will describe the effects of long term exposure to GH at the molecular level in the liver. Expression and activation of molecules involved in GH-induced signaling were analyzed in transgenic mice over-expressing GH (Miquet et al., 2008), as well as the influence of chronically elevated GH levels over EGFR signaling (González et al., 2010). Several signaling mediators involved in cellular proliferation, survival and migration are altered in the liver of these GH-transgenic mice. The molecular mechanisms underlying the pro-oncogenic pathology induced by prolonged exposure to elevated GH levels will be discussed. -Webb SM, Casanueva F &Wass JA 2002 Oncological complications of excess GH in acromegaly. Pituitary 5 21?25. -Jenkins PJ 2004 Acromegaly and cancer. Hormone Research 62 108?115. -Siegel G & Tomer Y 2005 Is there an association between acromegaly and thyroid carcinoma? 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